Can we delineate brain injury in full-term neonates using serum biomarkers?

OBJECTIVE: Early identification of neonates at risk of neurological impairment is particularly important for the bedside clinician. Clinical value of S100b and neuron-specific enolase in neonates has not been yet established. We investigated their kinetics and possible early clinical utility in neonatal encephalopathy (NE).STUDY DESIGN: 36 full-term neonates (13 with moderate/severe encephalopathy, 11 with mild encephalopathy, 12 controls) were enrolled and studied prospectively. Serum S100b and neuron-specific enolase (NSE) were measured serially on days(d) 1, 3, 9 and 18 of life. Brain MRI and long-term neurodevelopmental outcome were also assessed.RESULT: Neonates with moderate/severe encephalopathy had significantly increased S100b (d1) and NSE levels (d1, d3, d9) compared to controls. Neuron-specific enolase significantly correlated with the degree of encephalopathy, and a cutoff of 38.8 µg/l (d1) accurately predicted moderate/severe encephalopathy. S100b (d1) cutoff points of 1.6 µg/l and 11.4 µg/l prognosticated severe encephalopathy and death/cerebral palsy, respectively. Both biomarkers correlated well with neuroimaging and Bayley-III scores.CONCLUSION: Combined clinical, laboratory, imaging and neurodevelopmental data indicate that serum S100b and NSE can be useful biomarkers for the diagnosis and prognosis of neonatal brain injury, providing useful information to the bedside clinician.

Noninvasive Liver Fibrosis Tests in Patients with Nonalcoholic Fatty Liver Disease: An External Validation Cohort.

The main aim of this study was the comparative evaluation of nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), fibrosis 4 index (FIB-4), AST-to-Platelet Ratio Index (APRI), and enhanced liver fibrosis (ELF) test in distinguishing none/early (F0/F1) from significant/advanced (F2/F3) fibrosis in NAFLD patients, thereby providing an external validation cohort. Thirty-one patients with biopsy-proven NAFLD and 10 matched controls without NAFLD were prospectively enrolled. Serum hyaluronic acid (HA), aminoterminal propeptide of type III procollagen (PIIINP), tissue inhibitor of metallo-proteinases (TIMP)-1, and biochemical tests were measured. NFS, FIB-4, APRI, and ELF were calculated. ELF, FIB-4, and APRI, but not NFS, were higher in F2/F3 than F0/F1 group. Specifically, ELF [area under the ROC curve (AUROC): 0.86±0.10; p=0.004) and APRI (AUROC: 0.86±0.07; p=0.005], but not NFS (AUROC: 0.68±0.12; p=0.16), and FIB-4 (AUROC: 0.71±0.11; p=0.10), could similarly discriminate F0/F1 from F2/F3 stage. The sensitivity, specificity, positive predicted value (PPV), and negative predicted value (NPV) were: a) for cut-off of APRI=0.5, 85.7%, 70.8%, 46.2%, and 94.4%, respectively, and b) for cut-off of ELF=9.0, 85.7%, 83.3%, 60.0%, and 95.2%, respectively. When ln(PIIINP) or TIMP-1 were combined with APRI, the combined AUROCs could distinguish F2/F3 from F0/F1, but without significantly higher accuracy compared with APRI alone. APRI could also distinguish patients with simple steatosis from nonalcoholic steatohepatitis, and those with from those without lobular inflammation and ballooning, findings warranting further research. In conclusions: The application of ELF test and APRI can distinguish F0/F1 from F2/F3 fibrosis stages in NAFLD patients.

Thyroid function and autoimmunity during ovarian stimulation for intracytoplasmic sperm injection.

The aim of the present study was to assess changes in thyroid function and thyroid autoimmunity (TAI) throughout ovarian stimulation (OS) for intracytoplasmic sperm injection (ICSI) and the association of these changes with ICSI outcome. A flexible gonadotrophin-releasing hormone (GnRH) antagonist protocol was used in 42 women and their thyroid function and TAI were assessed at baseline and five times during OS (Days 3 and 5 of the menstrual cycle, the day of hCG administration, the day of ovum pick-up and the day of the pregnancy test). The primary outcome measure was the change in thyroid function throughout OS. No overall change was recorded in thyrotropin-stimulating hormone (TSH) concentrations throughout OS (P=0.066). In women who became pregnant (n=8), an increase in TSH concentrations was noted on the day of the pregnancy test compared with Day 3 of the menstrual cycle (3.410±1.200 vs 2.014±0.950µIU mL-1, respectively; P=0.001; mean ± s.d.). TAI was present in 11 of 42 women. Biochemical pregnancy was negatively correlated with changes in TSH (r=-0.7, P=0.004). No such association was noted regarding the live birth rate. The present study provides evidence that TSH concentrations could increase during OS, especially in women who become pregnant.

Comparative Effect of Atorvastatin and Rosuvastatin on 25-hydroxy-Vitamin D Levels in Non-diabetic Patients with Dyslipidaemia: A Prospective Randomized Open-label Pilot Study.

AIMS: Low 25-hydroxy-vitamin D [25(ΟΗ)D] levels have been associated with increased risk for cardiovascular disease. Conflicting data exist regarding the effect of statins on [25(OH)D] levels. The aim of this study was to compare the effect of atorvastatin and rosuvastatin on 25(OH)D levels in non-diabetic patients with dyslipidaemia. METHODS: This was a prospective randomized open-label study. Patients were assigned to atorvastatin 20 mg/day (n=28, age: 56.1±2.2 years, 22 females) or rosuvastatin 10 mg/day (n=24, age: 57.4±1.9 years, 20 females). Total cholesterol (TC), low- (LDL-C) and high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), fasting plasma glucose, insulin, glycosylated haemoglobin A1c (HbA1c) and high sensitivity C-reactive protein (hsCRP) levels were measured, and homeostatic model of assessment insulin resistance (HOMA-IR) was calculated at baseline and 12 weeks post-treatment. RESULTS: There were no within or between group significant differences in 25(OH)D levels (atorvastatin: 21.7±1.9 ng/ml at baseline and 23.5±2.3 ng/ml at week 12; rosuvastatin: 25.3±1.8 and 27.0±2.4 ng/ml, respectively; p=0.172 and p=0.306 for between groups, respectively). Both statins significantly reduced TC, TG and LDL-C levels, with a greater LDL-C reduction being observed by rosuvastatin. CONCLUSION: Atorvastatin and rosuvastatin did not significantly affect 25(OH)D levels in this study.

Sex steroids and sex hormone-binding globulin in postmenopausal women with nonalcoholic fatty liver disease.

OBJECTIVE: The evaluation of serum sex steroids and sex hormone-binding globulin (SHBG) levels in postmenopausal women with nonalcoholic fatty liver disease (NAFLD) and their association to the disease severity. DESIGN: Twenty-two postmenopausal women with biopsy-proven NAFLD and 18 matched controls were recruited. Blood samples for serum SHBG, total testosterone, estradiol levels and standard biochemical tests were obtained after overnight fasting. Free androgen index (FAI), calculated free (cFT) and bioavailable testosterone were estimated by standard formulas. RESULTS: The NAFLD group had lower serum SHBG levels and higher values of cFT, bioavailable testosterone and FAI, despite exhibiting similar to controls levels of serum total testosterone and estradiol. Serum SHBG levels (adjusted odds ratio [aOR]=0.912; 95% CI 0.854-0.973), bioavailable testosterone (aOR=1.254; 95% CI 1.010-1.556) and FAI (aOR=2.567; 95% CI 1.153-5.716), but not cFT, were associated with NAFLD independently of age, body mass index (BMI) and waist circumference. Serum estradiol levels were associated with the presence of nonalcoholic steatohepatitis (NASH) independently of age, BMI and waist circumference (aOR=0.727; 95% CI 0.537-0.985). CONCLUSIONS: Low SHBG levels and high metabolically active testosterone fractions were independently associated with NAFLD. Among NAFLD patients, serum estradiol levels were independently associated with NASH. However, these results need further validation from large-scale studies.

Comparison of the diagnostic accuracy of ischemia-modified albumin and echocardiography in patients with acute chest pain.

BACKGROUND: Several imaging tests and biomarkers have been proposed for the identification of patients with unstable angina among those presenting to the emergency department with acute chest pain. Preliminary data suggest that ischemia-modified albumin (IMA) may represent a potentially useful biomarker in these patients. OBJECTIVE: To compare IMA and echocardiography in excluding unstable angina in patients with acute chest pain. METHODS: Thirty-three patients (mean [± SD] age 59.8±10.8 years; 28 men) presenting to the emergency department with acute chest pain lasting <3 h suggestive of acute coronary syndrome, with normal or non-diagnostic electrocardiograms, and creatine kinase MB and troponin levels within the normal range, were included in the present study. RESULTS: After further diagnostic evaluation, five patients (15.2%) were diagnosed with unstable angina. The sensitivity, specificity, positive predictive value and negative predictive (NPV) value of echocardiography for diagnosing unstable angina was 60.0%, 89.3%, 50.0% and 92.6%, respectively. The area under the ROC curve for diagnosing unstable angina based on the serum IMA levels was 0.193 (95% CI 0.047 to 0.339; P<0.05). Based on ROC curve analysis, serum IMA levels ≥31.95 IU/mL yielded the optimal combination of sensitivity and specificity for diagnosing unstable angina. The sensitivity, specificity, positive predictive value and NPV of serum IMA levels ≥31.95 IU/mL for diagnosing unstable angina was 40.0%, 28.6%, 9.1% and 72.7%, respectively. CONCLUSIONS: Measurement of serum IMA levels appears to represent a useful tool for excluding unstable angina in patients presenting to the emergency department with acute chest pain. Moreover, IMA shows an NPV that is comparable with echocardiography.

Reduced bone mineral density in patients with haemophilia A and B in Northern Greece.

Haemophilia A and B has been associated with increased prevalence of low bone mass (67-86%). The aim of this study was to estimate the prevalence of bone disease in haemophiliacs and its association with potential risk factors. Adult patients with haemophilia A and B followed-up in the Haemophilia Centre of Northern Greece were included. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) in lumbar spine (LS), femoral neck (FN), total hip (TH) and great trochanter (GT). One-hundred four male patients (aged 45.8 ± 15.1 years) and 50 controls (aged 44.9 ± 12.8 years) were screened. Low BMD was diagnosed in 28 patients (26.9%) and 10 controls (20%) (p=0.0001). Patients had lower BMD in TH (p=0.007), FN (p=0.029) and GT (p=0.008) than controls, without differences in LS. BMD was positively associated with the severity of haemophilia, history of herpes virus C or human immunodeficiency virus and level of physical activity, and negatively with the level of arthropathy. In multiple-regression analysis, only the level of physical activity and 25-hydroxyvitamin D [25(OH)D] significantly predicted BMD. Half of the patients had vitamin D deficiency. In conclusion, our study showed increased prevalence of low BMD in haemophiliacs. The levels of physical activity and 25(OH)D independently predicted low BMD.

Serum vitamin B12 and folate levels in patients with non-alcoholic fatty liver disease.

The aim of the study was the evaluation of serum vitamin B12 and folate levels in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) and their association with the disease severity. Thirty patients with biopsy-proven NAFLD and 24 healthy controls matched for gender, age, body mass index and waist circumference were recruited. Blood samples for vitamin B12, folate, insulin and standard biochemical tests were obtained after overnight fasting. Homeostatic model of assessment-insulin resistance was calculated. There was no difference in serum vitamin B12 and folate levels between groups. Neither vitamin B12 nor folate levels were significantly different within any histological category, including steatosis grade, fibrosis stage, lobular inflammation, portal inflammation and ballooning. In conclusion, similar vitamin B12 and folate levels were observed in non-alcoholic steatohepatitis and non-alcoholic fatty liver patients, and controls. Furthermore, vitamin B12 and folate levels were not associated with either insulin resistance or the severity of liver disease.

Serum homocysteine levels in patients with nonalcoholic fatty liver disease.

Background and rational for the study. Nonalcoholic fatty liver disease (NAFLD) is regarded as the hepatic component of insulin resistance (IR) syndrome, but data on serum homocysteine (HCY) are limited. The aim of the study was the evaluation of serum HCY levels in patients with NAFLD. Material and methods. Thirty-one patients (54 ± 11 years, 8 males) with biopsy-proven NAFLD, 15 with simple nonalcoholic fatty liver (NAFL) and 16 with nonalcoholic steatohepatitis (NASH), and 22 healthy controls (52 ± 9 years, 5 males) matched for gender, age and body mass index (BMI), were recruited. Blood samples for HCY, folate, vitamin B12, insulin and standard biochemical tests were obtained after overnight fasting. Homeostatic model of assessment-insulin resistance (HOMA-IR) was calculated. Results. There was no difference in mean serum HCY levels between controls and NAFLD patients (12.6 ± 4.6 vs. 13.5 ± 2.6 mmol/L, respectively; p = 0.432). Serum folate and vitamin B12 were also similar between the study groups. Mean age, BMI, serum folate and vitamin B12 did not differ between NAFL and NASH patients. However, when compared with NAFL patients, NASH patients had lower mean serum HCY levels (12.3 ± 2.5 vs. 14.7 ± 2.1 mmol/L; p = 0.006). HCY was lower by increasing the grading of fibrosis (p = 0.005), portal inflammation (p = 0.029) and steatosis location (p = 0.021). In logistic regression analysis, HCY independently predicted NASH (p = 0.045) after adjustment for gender, age, BMI, AST, glucose and HOMA-IR. Conclusion. Our data suggest that serum HCY levels are lower in NASH compared with NAFL patients and can independently predict NASH. Serum HCY might represent another non-invasive marker for the assessment of NAFLD.

Thyroid dysfunction and long-term outcome during and after interferon-alpha therapy in patients with chronic hepatitis C.

INTRODUCTION: Thyroid dysfunction (TD) is a well-established adverse effect in chronic hepatitis C virus (HCV)-infected patients, treated with interferon-alpha (IFN-α), with or without ribavirin. However, the long-term outcome is not well-studied. The purpose of this study was to estimate the prevalence and long-term outcome of TD after HCV-therapy. MATERIALS AND METHODS: Retrospective analysis of 109 HCV-treated patients (for 6 to 12 months, according to HCV genotype), for the period 1996 to 2008. Thyroid function tests were performed every 3 months during therapy and after discontinuation (3 months to 12 years). Routine laboratory tests and virological assessment were performed according to generally accepted practice. RESULTS: TD was observed in 26 patients (23.85%). The positive and negative predictive value for thyroid autoantibodies (ATA) was 80% and 72.7%, respectively. Relative risk for those with positive ATA was 2.9 (95% CI: 1.6 to 5.3, P = 0.014). The median duration of TD was 12.0 months (min: 3; max: 132). The median follow-up period for the patients with TD was 25.5 months (min: 12; max: 144). Finally, 15 patients developed permanent TD (57.69%), compared to 11 with temporary TD (42.31%). Sex is a risk factor for TD, as there were more females than males affected (P = 0.011). Genotype, viral load, time of HCV-exposure prior to therapy, and virological response did not differ between patients with and without TD. CONCLUSION: TD among HCV-treated patients was more frequent than usually reported, with >50% developing permanent TD. ATA status may play a role in estimating the risk of subsequent TD. Women appear to be more vulnerable to TD than men.

Effect of spironolactone and vitamin E on serum metabolic parameters and insulin resistance in patients with nonalcoholic fatty liver disease.

AIM: The renin-angiotensin-aldosterone system has been implicated in the pathogenesis of insulin resistance and nonalcoholic fatty liver disease (NAFLD). The beneficial effect of spironolactone in a mouse model with diabetes and NAFLD has recently been reported. The main aim was assessment of the effect of spironolactone on serum metabolic parameters and insulin resistance in patients with NAFLD. METHODS: This study includes preliminary results of a single-centre randomised controlled trial of treatment with vitamin E (group 1, 10 patients) versus spironolactone plus vitamin E (group 2, 10 patients) in biopsy-proven NAFLD. Serum transaminases, lipids, potassium, sodium, glucose and insulin were measured, and homeostatic model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were calculated before and 8( )weeks after baseline assessment. RESULTS: Insulin was decreased within group 2 (15.3 ± 2.7 at baseline vs. 10.3 ± 5.0 at week 8, p = 0.013). Although no difference in glucose was observed, HOMA-IR significantly decreased (4.4 ± 0.9 vs. 2.8 ± 0.5, respectively, p = 0.047). QUICKI was increased, but not statistically significantly. CONCLUSIONS: Spironolactone and vitamin E combined therapy seems to exhibit a favourable effect on serum insulin and HOMA-IR in patients with NAFLD. If validated in a large-scale clinical trial, it may prove an inexpensive therapeutic approach for the management of NAFLD patients.

Thyroid dysfunction and long-term outcome during and after interferon-alpha therapy in patients with chronic hepatitis C

<p><b>INTRODUCTION</b>Thyroid dysfunction (TD) is a well-established adverse effect in chronic hepatitis C virus (HCV)-infected patients, treated with interferon-alpha (IFN-α), with or without ribavirin. However, the long-term outcome is not well-studied. The purpose of this study was to estimate the prevalence and long-term outcome of TD after HCV-therapy.</p><p><b>MATERIALS AND METHODS</b>Retrospective analysis of 109 HCV-treated patients (for 6 to 12 months, according to HCV genotype), for the period 1996 to 2008. Thyroid function tests were performed every 3 months during therapy and after discontinuation (3 months to 12 years). Routine laboratory tests and virological assessment were performed according to generally accepted practice.</p><p><b>RESULTS</b>TD was observed in 26 patients (23.85%). The positive and negative predictive value for thyroid autoantibodies (ATA) was 80% and 72.7%, respectively. Relative risk for those with positive ATA was 2.9 (95% CI: 1.6 to 5.3, P = 0.014). The median duration of TD was 12.0 months (min: 3; max: 132). The median follow-up period for the patients with TD was 25.5 months (min: 12; max: 144). Finally, 15 patients developed permanent TD (57.69%), compared to 11 with temporary TD (42.31%). Sex is a risk factor for TD, as there were more females than males affected (P = 0.011). Genotype, viral load, time of HCV-exposure prior to therapy, and virological response did not differ between patients with and without TD.</p><p><b>CONCLUSION</b>TD among HCV-treated patients was more frequent than usually reported, with >50% developing permanent TD. ATA status may play a role in estimating the risk of subsequent TD. Women appear to be more vulnerable to TD than men.</p>

Serum thyrotropin concentration as a biochemical predictor of thyroid malignancy in patients presenting with thyroid nodules.

PURPOSE: Serum thyrotropin (TSH) is a well-established growth factor for thyroid nodules and suppression of TSH concentrations by administering exogenous thyroxine may interfere with the growth of established nodules as well as the formation of new thyroid nodules. The aim of this study was to investigate whether serum TSH at presentation is a predictor of thyroid malignancy in patients with thyroid nodules. METHODS: A total of 565 patients without overt thyroid dysfunction, who presented with palpable thyroid nodule(s) between 1988 and 2004 and underwent at least one fine-needle aspiration biopsy, were retrospectively evaluated. RESULTS: The final diagnostic outcome was established after surgery (n = 122) or after a minimum of 1-year clinical follow-up period. Higher rates of malignancy were observed in patients with serum TSH in the upper tertile of the normal range (P = 0.026). Binary logistic regression analysis revealed significantly increased adjusted odds ratios for the diagnosis of malignancy in patients with serum TSH 1.5-4.0 mIU/l when compared to those with either TSH 0.4-0.8 mIU/l (P = 0.005) or TSH 0.9-1.4 mIU/l (P = 0.007). CONCLUSIONS: The risk of malignancy in thyroid nodules increases in parallel with TSH concentrations within the normal range. TSH concentration at presentation is an independent predictor of thyroid malignancy.